Before patients develop myeloma, they pass through two earlier disease stages known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Part of the diagnostic work-up involves careful determination of where a patient is along this spectrum from MGUS to active multiple myeloma.


The earliest stage of myeloma is not cancer at all, but a benign condition called monoclonal gammopathy of undetermined significance, or MGUS (pronounced "EM-guss").

  • People who have MGUS have a low level of a type of blood protein (monoclonal protein, also called M-protein) and a low level of abnormal plasma cells in the bone marrow, but have no indicators of active disease.
  • While all patients with myeloma had MGUS before they developed active disease, only 20% of patients with MGUS actually progress to active myeloma.
  • The risk of a patient's progression from MGUS to active myeloma is only 1% per year. 

Patients with MGUS should be followed by a hematologist/oncologist but are rarely treated unless they choose to participate in a clinical trial.


Smoldering multiple myeloma (SMM) is an asymptomatic, intermediate stage of myeloma between MGUS and active, symptomatic myeloma.

  • While patients with SMM have a higher level of monoclonal protein and more abnormal plasma cells in the bone marrow than patients with MGUS, SMM causes no CRAB criteria (damage to red blood cells, kidneys, or bones).
  • SMM is not a single entity, but a spectrum of different stages of disease with three distinct possibilities:
  1. MGUS with an increased but stable number of abnormal plasma cells.
  2. Minimally progressive myeloma without CRAB criteria or myeloma-defining events.
  3. Moderately progressive myeloma, but with no damage to red blood cells, kidneys, or bones.
  • SMM patients are carefully monitored at regular intervals based on the patient's status and the doctor's judgment. Be sure to tell your doctor about any changes in your health status.
  • The risk of progression to active myeloma for patients with standard-risk SMM is 10% per year for the first five years, 3% per year for the next five years, and 1%-2% per year for the next 10 years.
  • While the current standard of care for SMM is not to treat the patient but to "watch and wait," there are many clinical trials to treat patients with SMM and "high-risk" SMM before their disease progresses.
  • A hematologist/oncologist's judgment and experience are crucial in distinguishing SMM from MGUS and active myeloma. We recommend a consultation with a myeloma specialist to avoid either unnecessary or delayed treatment.



  • Active myeloma is diagnosed either because certain specific tests indicate that there is a risk of progression to CRAB criteria (damage to bones, red blood cells, and/or kidneys, defined below) within 18 months to two years, or because the patient already has one or more of the CRAB criteria.
  • Until 2014, patients were not diagnosed with myeloma unless they had one or more of the CRAB criteria. In 2014, the IMF's research arm, the International Myeloma Working Group (IMWG), published new diagnostic criteria based on biological markers that could predict that one or more of the CRAB criteria would occur within 18 months to two years in patients with "ultra-high-risk myeloma." These biological markers are called "myeloma-defining events" (MDE).
  • What was formerly called "ultra-high-risk myeloma" was redefined as "early active myeloma" that should be treated.


Definitions of MGUS, SMM, and Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) · Monoclonal protein present but usually ‹ 3.0 g/dL
· No CRAB features or other indicators of active myeloma
· Bone marrow monoclonal plasma cells ‹ 10%
Smoldering multiple myeloma (SMM) · Higher level of disease than MGUS: serum M-component can be › 3.0 g/dL and/or bone marrow plasma cells › 10%, but
· No CRAB features or other indicators of active myeloma
Myeloma based on MDE · ≥ 60% bone marrow plasma cells
· Free light chain ratio ≥ 100
· > 1 MRI focal lesion
Myeloma based on CRAB · Monoclonal protein present, and
· One or more CRAB features and/or indicators of organ damage

*Organ damage classified as "CRAB" or any other significant clinical problem linked to myeloma progression such as recurrent infections or neuropathy unrelated to treatment.

C - Calcium elevation (> 10mg/dL).

R - Renal dysfunction (creatinine > 2mg/dl or creatinine clearance (< 40ml/min).

A - Anemia (hemoglobin < 10g/dL or > 2g/dL decrease from patient's normal).

B - Bone disease (one or more osteolytic lesions detected on skeletal radiography, WBLC CT or PET/CT).

One or more "CRAB" features or other significant problem required for diagnosis of symptomatic myeloma.


New Definitions of Myeloma and Early Myeloma

Myeloma is a cancer of the plasma cells, white blood cells that normally make antibodies (complex proteins called "immunoglobulins" in medical terminology) to fight substances such as bacteria and viruses that the body recognizes as foreign.

Myeloma cells, unlike healthy plasma cells, cannot make functioning antibodies. Instead, they make an abnormal immunoglobulin known as "monoclonal protein." The result is a reduced ability to fight infection, but there are many other medical problems that can arise within the bone marrow, where myeloma normally grows, and outside the bone marrow.


Multiple Myeloma Definitions and Staging


Medical Problems Related to Myeloma

Effects of Increased Myeloma Cells
in the Bone Marrow

CRAB criteria


Cause Impact on Patient
C - Increase in blood calcium Release of calcium from damaged bone into bloodstream.
  • Mental confusion
  • Dehydration
  • Constipation
  • Fatigue
  • Weakness
  • Renal or kidney damage
R -Renal problems in kidney damage Abnormal monoclonal proteins produced by the myeloma cells are released into the bloodstream and can pass into the urine and produce kidney damage. High blood calcium, infections, and other factors can also cause or increase the severity of kidney damage.
  • Sluggish circulation
  • Fatigue
  • Mental confusion
A - Anemia Decrease in the number and activity of red blood cell-producing cells in the bone marrow.
  • Fatigue
  • Weakness
B - Bone Damage
  • Thinning (osteoporosis) or
  • Areas of more severe damage (called lytic lesions), fracture, or collapse of a vertebra
The myeloma cells activate osteoclast cells, which destroy bone, and block osteoblast cells, which normally repair damaged bone.
  • Bone pain
  • Bone swelling
  • Fracture or collapse of a bone
  • Nerve or spinal cord damage
Additional types of organ dysfunction Local or systemic effects of myeloma, other than CRAB features.
  • Neuropathy
  • Recurrent infections
  • Bleeding problems
  • Other individual problems
Abnormal immune function The myeloma cells reduce the number and activity of normal plasma cells capable of producing antibodies against infection.
  • Susceptibility to infection
  • Delayed recovery from infection

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